May 14, 2012 – A new study by CHORI scientists identifies how skeletal muscle stem cells respond to muscle injury and may be stimulated to improve muscle repair in Duchenne Muscular Dystrophy (DMD). A severe inherited disease of muscle that causes weakness, disability and ultimately heart and respiratory failure, patients with DMD have a limited life expectancy of less than 30 years. A new study, led by CHORI Senior Scientist Julie Saba, MD, PhD, however, has shown for the first time that a lipid signaling molecule called sphingosine-1-phosphate, or S1P,
can trigger an inflammatory response that stimulates the muscle stem cells to proliferate and assist in muscle repair.
"We were able to show that boosting S1P levels in a mouse model with a disease very similar to DMD significantly improved muscle regeneration," says Dr. Saba."These findings are important especially for certain muscle diseases, or myopathies, like DMD, that can affect
|“We were able to show that boosting S1P levels in a mouse model with a disease very similar to DMD significantly improved muscle regeneration.”
DMD is the most common and one of the most degenerative muscle diseases. Most commonly occurring in young boys, it often leads to death from respiratory and heart failure in a patient's twenties.
Skeletal muscle is the biggest organ system of the human body and is important for all human activity. Muscles can be injured by trauma, inactivity, aging and a variety of inherited muscle diseases, like DMD, in which the muscles degenerate over time. Importantly however, skeletal muscle is one of the few tissues of the human body that has the potential to fully repair itself after injury. The ability of muscles to regenerate themselves is attributed to the presence of a form of adult stem cells called satellite cells that are essential for muscle repair.
According to the study, waking up the cells
involves the ability of S1P to activate S1P receptor 2, one of its five cell surface receptors, leading to
downstream activation of an inflammatory pathway controlled by a transcription factor called
STAT3. The results showed that S1P is rapidly produced in the muscle immediately after injury, leading to
an S1P "signal." S1P, acting through S1P receptor 2, leads to activation of STAT3, resulting in
changes in gene expression that cause the satellite cell to leave its "sleeping" state and start to
proliferate and assist in muscle repair.
|“Normally, satellite cells lie quietly at the periphery of the muscle fiber and do not grow, move or become activated. However, after muscle injury, these stem cells "wake up" and fuse with the injured muscle, to rebuild healthy muscle fiber.”
"Normally, satellite cells lie quietly at the periphery of the muscle fiber and do not grow, move or become activated," explains Dr. Saba. "However, after muscle injury, these stem cells "wake up" through unclear mechanisms and fuse with the injured muscle, stimulating a complicated process that results in the rebuilding of a healthy muscle fiber."
A signaling molecule that controls the movement and proliferation of many human cell types, S1P was known to be involved in satellite cell activation. In the latest study, however, published on May 14th in the Public Library of Science One (PLoS ONE), Dr. Saba and her colleagues have shown for the first time the mechanisms by which S1P is able to wake up the stem cells at the time of injury.
"We found that mdx mice, which have a
disease similar to DMD, are deficient in S1P. We were able to increase the
S1P levels in the mice using a drug that blocks S1P breakdown," says Dr. Saba. "This treatment increased the number
of satellite cells in the muscles and improved the efficiency of muscle regeneration after injury."
If these findings are also found to be true in humans with DMD, it may be
possible to use similar approaches to boost S1P levels in order to improve satellite cell function and
muscle regeneration in patients with the disease. Drugs that block S1P metabolism and boost S1P
levels are now being tested for the treatment of other human diseases including rheumatoid arthritis.
If these studies prove to be relevant in DMD patients, it may be possible to use the same drugs
to improve muscle regeneration in these patients. Alternatively, new agents that can specifically
activate S1P receptor 2 could also be beneficial in recruiting satellite cells and improving muscle
regeneration in muscular dystrophy and potentially other diseases of muscle.
Thursday, May 17, 2012 3:26 PM